Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis

Osteopetrosis is a heterogeneous group of inherited disorders that includes a malignant autosomal recessive forrn, an intermediate autosomal recessive form and autosomal dominant forms of the disease. Most malignant osteopetroses have been ascribed to mutations in the OC116 gene encoding the human a3 subunit of vacuolar H(+)-ATPase. Few cases of autosomal recessive malignant osteopetrosis have been ascribed to mutations in the chloride channel 7 gene (CLCN7), which accounts for all autosomal dominant type II cases reported to date. Up until now, however, nothing has been known regarding the molecular basis of the intermediate form of osteopetrosis (IARO). Our study of two Portuguese IARO families shows that homozygosity for C1CN7 mutations also accounts for this form of osteopetrosis. The two patients presented with spontaneous fractures in the first years of life and generalised increase of bone density. Direct sequencing of the C1CN7 gene in both patients revealed homozygosity for two mutations (G203D and P470Q). We conclude therefore that C1CN7 mutations not only account for some dominant and malignant forms but also for intermediate forms of osteopetrosis.